Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency.

BACKGROUND: Congenital sphingosine-1-phosphate (S1P) lyase deficiency due to biallelic mutations in SGPL1 gene has recently been described in association with primary adrenal insufficiency and steroid-resistant nephrotic syndrome. S1P lyase, on the other hand, is therapeutically inhibited by fingolimod which is an oral drug for relapsing multiple sclerosis (MS). Effects of this treatment on adrenal function has not yet been evaluated. We aimed to test adrenal function of MS patients receiving long-term fingolimod treatment. METHODS: Nineteen patients (14 women) with MS receiving oral fingolimod (Gilenya®, Novartis) therapy were included. Median age was 34.2 years (range; 21.3-44.6 years). Median duration of fingolimod treatment was 32 months (range; 6-52 months) at a dose of 0.5 mg/day. Basal and ACTH-stimulated adrenal steroid measurements were evaluated simultaneously employing LC-MS/MS based steroid panel. Basal steroid concentrations were also compared to that of sex- and age-matched healthy subjects. Cortisol and 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone were used to assess glucocorticoid, mineralocorticoid and sex steroid producing pathways, respectively. RESULTS: Basal ACTH concentrations of the patients were 20.8 pg/mL (6.8-37.8 pg/mL) (normal range; 5-65 pg/mL). There was no significant difference in the basal concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone between patients and controls (p = 0.11, 0.058, 0.74, 0.15; respectively). All patients showed adequate cortisol response to 250 mcg IV ACTH stimulation (243 ng/mL, range; 197-362 ng/mL). There was no significant correlation between duration of fingolimod treatment and basal or ACTH-stimulated cortisol or change in cortisol concentrations during ACTH stimulation test (p = 0.57, 0.66 and 0.21, respectively). CONCLUSION: Modification and inhibition of S1P lyase activity by the long-term therapeutic use of fingolimod is not associated with adrenal insufficiency in adult patients with MS. This suggests that S1P lyase has potentially a critical role on adrenal development rather than the function of a fully mature adrenal gland.

Revisiting Classical 3ß-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases.

CONTEXT: The clinical effects of classical 3ß-hydroxysteroid dehydrogenase 2 (3ßHSD2) deficiency are insufficiently defined due to a limited number of published cases. OBJECTIVE: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3ßHSD2 deficiency. DESIGN: Multicenter, cross-sectional study. SETTING: Nine tertiary pediatric endocrinology clinics across Turkey. PATIENTS: Children with clinical diagnosis of 3ßHSD2 deficiency. MAIN OUTCOME MEASURES: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3ßHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. RESULTS: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ±â€…5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3ßHSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. CONCLUSIONS: Genetically-documented 3ßHSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3ßHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3ßHSD2 deficiency.